1. Field of the Invention
The present invention relates to novel trichothecene derivatives, to processes for their production and to their use as antitumor agents for the inhibition of malignant tumors in mammals.
2. Description of the Prior Art
The trichothecene derivatives of the present invention in general contain a 9,10 double bond and a 12,13-epoxy function. The basic skeleton and numbering system for this class of trichothecenes is shown below. ##STR1## Various examples of both naturally occurring and semisynthetic compounds of this class have been described in the literature. Illustrative of the more relevant publications are the following:
1. The compound anguidine (also called diacetoxyscirpenol) having the formula ##STR2## is disclosed as an antitumor agent in U.K. Pat. No. 1,063,255. Phase I clinical trials of anguidine in the United States have been reported in Proc. Amer. Assoc. Cancer Res. 17:90 (1976) and Proc. Amer. Assoc. Cancer Res. 18:296 (1977). Also disclosed (at least generically) are various derivatives of anguidine such as anguidol (also called scirpentriol or 3.alpha.,4.beta.,15-trihydroxy-12,13-epoxytrichothec-9-ene), monodesacetylanguidine (presumably 15-acetoxy-3.alpha.,4.beta.-dihydroxy--12,13-epoxytrichlothec-9-ene or monoacetoxyscirpendiol) and esters of anguidine, anguidol and monodesacetylanguidine.
Monoacetoxyscirpenol and certain esters of scirpentriol (not including any of the presently claimed compounds) are also disclosed in J. Agric. Food Chem. 24(1):97-103 (1976) as mycotoxins.
2. Japanese Published Applications J4 9,134,891 and J4 9,134,892 disclose T2 and HT2 toxins of the formula ##STR3## wherein R is --OH or ##STR4## The compounds are said to be useful as antiviral agents.
3. U.S. Pat. No. 4,129,577 discloses anguidine derivatives of the formula ##STR5## wherein R.sub.1 is H or ##STR6## and R is an alkyl or aromatic group or is an acyl group ##STR7## in which R.sup.1 is an aliphatic, cycloaliphatic or aromatic group or a carbamate group --CONH--R.sup.1. The compounds are useful as cytotoxic agents.
4. U.S. Pat. No. 3,428,652 discloses anguidine derivatives of the formula ##STR8## wherein R.sub.1 is H and R.sub.2 is methyl or, R.sub.1 and R.sub.2 together represent propylene, and Hal is Cl, Br or I. The compounds are reported to have antitumor activity.
5. The 12,13-epoxytrichothecenes of the general formula ##STR9## wherein R.sup.1 and R.sup.3 are H, OH or esterified OH and R.sup.2 is OH, .dbd.O or esterified OH are described in Biochemical and Biophysical Research Communications 57(3):838-844 (1974) as inhibitors of protein synthesis. None of the ester derivatives of the present invention are disclosed in this publication.